Base-Induced Sulfoxide-Sulfenate Rearrangement of 2-Sulfinyl Dienes for the Regio- and Stereoselective Synthesis of Enantioenriched Dienyl Diols

The base-induced [2,3]-sigmatropic rearrangement of a series of enantiopure 2-sulfinyl dienes has been examined and optimized using a combination of NaH and iPrOH. The reaction takes place by allylic deprotonation of the 2-sulfinyl diene to give a bis-allylic sulfoxide anion intermediate that after protonation undergoes sulfoxide-sulfenate rearrangement. Different substitution at the starting 2-sulfinyl dienes has allowed us to study the rearrangement finding that a terminal allylic alcohol is determinant to achieve complete regioselectivity and high enantioselectivities (90:10–95:5) with the sulfoxide as the only element of stereocontrol. Density functional theory (DFT) calculations provide an interpretation of these results.


■ INTRODUCTION
The rich chemistry of allylic sulfoxides along with their presence in natural products places them among the more interesting organosulfur motifs. 1 One of their more versatile reactions is the [2,3]-sigmatropic rearrangement that allows for the transformation of allylic sulfoxides into allylic sulfenates and subsequently into allylic alcohols, in the presence of a suitable thiophile to cleave the sulfenate S−O bond. In this process, the stereochemistry is transferred from the C−S bond of the allylic sulfoxide to the new C−O bond in the final product (Scheme 1a). 2 This reaction commonly referred to as sulfoxide-sulfenate or Mislow−Evans rearrangement has attracted the attention of chemists from a mechanistic 3 and a synthetic standpoint. 4 In particular, the [2,3]-sigmatropic rearrangement of allylic sulfoxides is a versatile tool in the synthesis of numerous target compounds because it can easily be coupled to other reactions such as 1,2-elimination, other sigmatropic rearrangements, Knoevenagel condensation (SPAC) and [4+2] cycloadditions. 2a In this context, during the last years, our group has developed the diastereoselective Michael-type addition to 1and 2-sulfinyl dienes (1 and 2) to generate transient allylic sulfoxides I that evolved through [2,3]-sigmatropic rearrange-ment (Scheme 1b). We have applied this tandem process intramolecularly for the stereoselective synthesis of enantiopure functionalized dihydropyrans 5 and tetrahydropyridinols 6 as well as intermolecularly for the synthesis of acyclic 2-ene-1,4-diols, 7 1,4-aminoalcohols, 8 and 1,4-hydroxysulfides 9 with a high degree of stereocontrol.
Within this study and upon examination of the addition of alkoxides (NaOBn) to 2-sulfinyl dienes having alkyl substituents (1a, R = n-Bu), we identified the expected product 3 along with dienyl diol 4, presumably formed by allylic deprotonation of the 2-sulfinyl diene to give a bis-allylic sulfoxide anion intermediate (II) that after protonation underwent a completely regioselective sulfoxide-sulfenate rearrangement toward the allylic alcohol double bond. Interestingly, 4 was isolated as a single product by treatment with base in the absence of alkoxide and lowering the reaction temperature (−40°C to rt) with moderate yield (57%) and 92:8 enantiomeric ratio, 7 remarkably high for the sulfoxide as the only element of stereocontrol. Encouraged by our previous result, we envisioned that treating with base a group of 2sulfinyl-dienes 1, selected by addressing the nature of R 1 and R 2 , the stereochemistry of the double bonds, and the degree of substitution (Table 1, R 3 , R 4 ), would give us the opportunity to study the regioselectivity of the [2,3]-sigmatropic rearrangement of bis-allylic sulfoxide intermediates and to explore the synthesis of dienyl diols 4, valuable compounds in natural products and as synthetic intermediates 10 (Scheme 1c). In spite of the widespread successful use of the sulfoxide-sulfenate rearrangement in synthesis, we could not find studies where both the regio-and enantioselectivities of the process were examined. Herein, we disclose a full account of our findings. ■ RESULTS AND DISCUSSION Synthetic Studies. Selected 2-sulfinyl dienes were synthesized by the general and efficient Stille coupling of vinyl stannanes or boronates with (Z)-or (E)-iodo vinyl sulfoxides previously obtained from (−)-menthyl p-toluenesulfinate in three steps (Table 1). 11 We prepared 2-sulfinyl dienes having a hydroxyl group at R 2 (1a−1j, and 1o-q) with different degree of substitution (1c, 1d, 1g, 1o-q) and distance from sulfoxide to the OH group (1i, 1j). Substrates with a protected hydroxyl group (1k), a tertiary amine (1l), or lacking the OH (1m and 1n) in R 2 were also chosen to examine regioand enantioselectivities of the rearrangement. Finally, we also considered variations at R 1 by introducing an additional double bond (1h), functionalized alkyl chains (1e−1g), and also by preparing (E,E)-and (E,Z)-dienes (1a and 1c vs 1b and 1d) to examine the effect of the stereochemistry of the sulfinyl diene on the outcome of the process.
To optimize the conditions of the base-promoted [2,3]rearrangement of 2-sulfinyl diene 1a, we examined its reactivity with an excess of NaH in toluene ( Table 2, entries 1−3) finding that 4a was formed with complete regioselectivity and that both isolated yield and reactivity decreased by lowering the reaction temperature while the enantiomeric ratio increased from 86:14 to 92:8. Er dropped to 70:30 using tetrahydrofuran (THF) as solvent (Table 2,entry 4). At this point, we examined the influence of external thiophiles such as Et 2 NH using different bases (Table 1, entries 5−8), but we did not observe any improvement in yield or er. In our experience, 7 alkoxides are efficient thiophiles in related sulfoxide-sulfenate rearrangements; therefore, we added 2 equiv of i PrOH to generate hindered NaO i Pr that would not undergo Michael addition to 1a but could improve the yield of the reaction. After some experimentation with different bases (Table 2, entries 9−11), we found that the combination NaH/ i PrOH produced a notable increase in reactivity with a higher yield (62%) and 93:7 er at rt. Subsequently, we applied the optimized conditions to the set of 2-sulfinyl dienes previously synthesized (Table 1) and the results are gathered in Table 3. In general, (E,Z)-2-sulfinyl dienes with a hydroxymethyl in R 2 and a simple alkyl group in R 1 (1a, 1e, 1f) reacted in 2 h with complete regioselectivity toward the allylic alcohol fragment affording 4a, 4c, and 4d  We also observed complete regioselectivity when an additional conjugated double bond is present in the starting material (1h); however, a decay in yield and enantiomeric ratio was observed (4f). Increasing the distance between sulfoxide and OH (1i) resulted in a slower reaction (21 h) and a decrease in regioselectivity (4g:5g, 88:12) maintaining a good er only for 4g (95:5). A similar trend was found for 1j with a sluggish reaction and a higher decay in yield and regioselectivity affording a complex mixture that decomposed under purification giving only a small amount of 4h. Installation of a TIPS protecting group (1k) led to a mixture of products where small amounts of isomeric sulfinyl trienes, resulting from the elimination of the silyloxy moiety, were tentatively identified.
Next, we examined the base-induced sulfoxide-sulfenate rearrangement on 2-sulfinyl dienes 1r and 1s, with an additional hydroxyl group in R 1 , which can compete by intramolecular Michael addition, smoothly prepared by acidic desilylation of 1e and 1f (Scheme 2). Upon treatment with NaH/ i PrOH in toluene, both substrates underwent intramolecular conjugate addition of the distal alkoxide onto the dienyl sulfoxide followed by [2,3]-sigmatropic rearrangement to render tetrahydrofuran 8 and tetrahydropyran 9 with moderate yields and an 80:20 anti:syn diastereostereoselectivity (measured by integration of the 1 H NMR as (S)-MPA esters 10 and 11, not shown). The enantiomeric ratios found (80:20 for the major anti diastereomer), lower than in previously studied intermolecular reactions, could be tentatively attributed to partial racemization of the sulfinyl group upon deprotection under acidic conditions with AcCl in MeOH.
Finally, to illustrate the synthetic versatility of dienyl diols 4 accessible by our sequence, we addressed the chemoselective propargylation of the secondary hydroxyl group in 4b to afford 12, which underwent an intramolecular [4+2] cycloaddition upon treatment with a catalytic amount of CuI and Et 3 N, 13 affording tetrahydroisobenzofuran 13 with complete diastereoselectivity and in 80% yield (Scheme 3).
Theoretical Calculation at the Density Functional Theory (DFT) Level. To gain further understanding of the origin and influence of substituents on the regio-and stereoselectivities observed, the possible intermediates and transition states derived from selected model structures were studied by DFT calculations. 14 Figure 2a shows the structure of model I, a bis-allyl sulfoxide derived from the deprotonation/protonation of a linear alkyl substituted diene that could be used as a model for 1m. Considering the excess of base required for the reaction and the high conformational freedom expected for the intermediate anions, 15 the protonation and subsequent transition states for the sigmatropic rearrangement were analyzed to occur through both faces of the diene leading to equally stable bis-allyl sulfoxides (structures a and b). Under the reaction conditions, the source of protons is uncertain. Quenching the reaction with MeOH-d 4 or D 2 O does not lead to any deuteration in the final compounds; therefore, we hypothesized that the sigmatropic rearrangement takes place on allylic sulfoxides rather than on the anionic species and protonation could derive from other molecules of diene since no deuteration of 4a was observed when the reaction of 1a was performed in toluene-d 8 either in the presence or absence of i PrOH ( Table 2, entries 2 and 11).
Thus, the regioselectivity observed seems to be determined by the relative energy between TSIa-endo and TSIb-endo 3a that predicts a ratio of 70:30 in relatively good agreement with experimental result. The higher stability of TSIa-endo against TSIb-endo could be related to the low steric hindrance exerted by the methyl group close to the bond being formed. This trend could also explain the reverse selectivity observed in the case of diene 1n (4k:5k, 20:80).
Model II, with a hydroxyl group, could be used as a model for 1a (Figure 2b). Under the reaction conditions, the most important intramolecular stabilizing interactions are the coordination of the sodium alkoxide to the sulfoxide oxygen or to the aromatic ring depending on the conformation around the C−S bond. The difference in energy between TSIIa-endo and TSIIb-exo (2.4 kcal·mol −1 ) predicts a ratio of 98:2 in good agreement with experimental stereoselectivity observed. On the other hand, the relative energy between TSIIa-endo and TSIIb-endo would explain the complete regioselectivity observed in the reaction of 1a.
The introduction of an additional methylene group between the olefinic carbon and the hydroxyl group yields III (model for 1i, Figure 2c). Although the most important intramolecular stabilizing interactions are the same as in model II, the increase  in cycle size results in an increase in possible conformations, of which the most stable for each approach are shown in the figure. According to the data, although the stereoselectivity of the main compound could be justified as in the previous model, the high instability of TSIIIb-endo does not account for the formation of the minor regioisomer experimentally observed, suggesting a more complex model could be involved in this case. Additionally, according to these calculations, the presence of a hydroxyl group in the molecule does not translate into a decrease of the activation barrier for the sigmatropic rearrangement (compare relative energies for the most stable endo TSs in Figure 2a−c). Therefore, the experimental observation of an increase in the reaction speed when a hydroxyl group is present could be related to the formation of the corresponding alkoxide that could work as a directing group favoring the approach of the base to form the carbanion.
In summary, we have designed a series of 2-sulfinyl dienes having different substitutions for the study of the base-induced [2,3]-sigmatropic rearrangement. After allylic deprotonation/ protonation, the bis-allylic sulfoxide intermediate undergoes sulfoxide-sulfenate rearrangement to afford dienyl diols 4. The presence of an allylic alcohol is determinant for the good reactivity of 2-sulfinyl dienes and to achieve complete regioselectivity and high enantioselectivity (90: 10−95:5) with the sulfoxide group as the only element of stereocontrol. ■ EXPERIMENTAL SECTION General Section. Reagents and solvents were handled using standard syringe techniques. All reactions were carried out under an argon atmosphere. Anhydrous solvents (toluene, CH 3 CN, CH 2 Cl 2 , Et 2 O, THF, and DMF) were purified by filtration on a solvent purification system. So-collected toluene was stored over CaH 2 . Oilfree NaH and KH were obtained from the NaH or KH/mineral oil mixture that was carefully washed with hexane and dried prior to use. Crude products were purified by flash chromatography on 230−400 mesh silica gel with distilled solvents. Analytical thin-layer chromatography (TLC) was carried out on silica gel plates with detection by UV light, iodine, ninhydrin solution in ethanol, and 10% phosphomolybdic acid solution in ethanol. All reagents were commercial products. Through this section, the volume of solvents is reported in mL/mmol of starting material. 1 H and 13 C NMR spectra were recorded at 300, 400, or 500 MHz ( 1 H) using CDCl 3 as solvent unless otherwise indicated and with the residual solvent signal as internal reference unless otherwise noted. The following abbreviations are used to describe peak patterns when appropriate: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), ap (apparent). Optical rotations were measured at 20°C using a sodium lamp and in CHCl 3 solution unless otherwise stated. High-resolution mass spectra (HRMS) were recorded using Accurate Mass quadrupole time-of-flight (Q-TOF), liquid chromatography/ mass spectrometer (LC/MS), Agilent Technologies 6520 spectrometer.
Synthesis of Starting Materials. Synthesis of (E)-Vinyl Stannanes. Unless otherwise noted, vinyl stannanes were prepared following this modified procedure: A dry two-neck round-bottom flask fitted with a reflux condenser was charged with commercially available hydroxy alkyne (1 equiv) and AIBN (0.01 equiv) under argon and anhydrous toluene was added (1 mL × mmol). The mixture was heated at 115°C using an oil bath, and then a solution of Bu 3 SnH (1.5 equiv) and AIBN (0.04 equiv) in toluene (1 mL × mmol) was added dropwise, maintaining a moderate reflux until disappearance of starting material (TLC, 4 h). The solvent was removed, and the crude product was purified by column chromatography on silica gel 5−20% (Et 2 O-hexane) to afford (E)vinyl stannanes as colorless oils (15−20% of regio-and stereoisomers were identified in the crude mixtures).
General Procedure for the Synthesis of Iodo Vinyl Sulfoxides. To a solution of I 2 (1.2 equiv) in CH 2 Cl 2 (6 mL/mmol sulfoxide) at rt under argon was added a solution of sulfinyl vinyl stannanes (1.0 equiv) in CH 2 Cl 2 (5 mL/mmol sulfoxide). The mixture was stirred at rt until disappearance of starting material (TLC, 40 min), and then it was quenched with a Na 2 S 2 O 4 solution (2 mL/mmol, 1 M) and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 4 mL/mmol sulfoxide). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure, and the crude was purified by column chromatography on silica gel.
Method A. A degassed solution of iodo vinyl sulfoxide (1.0 equiv), vinylstannane (1.3 equiv), BHT (1.0 equiv), Ph 3 As (0.1 equiv), and Pd 2 (dba) 3 ·CHCl 3 (0.05 equiv) in THF 10 mL/mmol of iodo vinyl sulfoxide) was stirred under Ar and at rt until disappearance of the starting material (TLC). The solvent was removed under vacuum, and the crude residue was purified by chromatography on silica gel.
Method B. A degassed solution of iodo vinyl sulfoxide (1.0 equiv), vinylstannane (1.3 equiv), and Pd(CH 3 CN) 2 Cl 2 (0.1 equiv) in DMF (2.5 mL/mmol of iodo vinyl sulfoxide) was stirred under Ar and at rt until disappearance of the starting material (TLC). Then, it was filtered through celite and the solution was concentrated in vacuo.
The crude material was purified by column chromatography on silica gel.
Method D. To a 0°C solution of 1.0 equiv of 2-sulfinyl diene 1e or 1f in MeOH (6 mL/mmol), acetyl chloride (0.3 equiv) was added. The mixture was stirred under Ar and warmed up to room temperature until disappearance of the starting material (TLC). CHCl 3 and a saturated solution of NaHCO 3 (10 mL/mmol sulfinyl diene) were added to the reaction mixture, and then it was stirred for 5 min. The aqueous layer was extracted with CHCl 3 (4 × 5 mL), and the combined organic layers were washed with saturated NaCl solution, dried over MgSO 4 , filtered, and concentrated under vacuum to obtain a crude product that was purified by column chromatography on silica gel using EtOAc as eluent.